Antiviral agents

ABSTRACT

The present invention provides antiviral compounds of formula (I), 
                         
as well as pharmaceutical compositions comprising these compounds, methods for synthesizing these compounds and methods of using these compounds for treating a viral infection.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.61/307,115, filed Feb. 23, 2010. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel antiviral agents, compositionscontaining them, processes for their preparation, intermediates in theirsynthesis, and their use as therapeutics for prevention of organtransplantation rejection, the treatment of immune disorders andinflammation, and treatment of viral (particularly heptitis C viral)infection.

BACKGROUND OF THE INVENTION

Infection with HCV is a major cause of human liver disease throughoutthe world. In the US, an estimated 4.5 million Americans are chronicallyinfected with HCV. Although only 30% of acute infections aresymptomatic, greater than 85% of infected individuals develop chronic,persistent infection. Treatment costs for HCV infection have beenestimated at $5.46 billion for the US in 1997. Worldwide over 200million people are estimated to be infected chronically. HCV infectionis responsible for 40-60% of all chronic liver disease and 30% of allliver transplants. Chronic HCV infection accounts for 30% of allcirrhosis, end-stage liver disease, and liver cancer in the U.S. The CDCestimates that the number of deaths due to HCV will minimally increaseto 38,000/year by the year 2010.

There are considerable barriers to the development of anti-HCVtherapeutics, which include, but are not limited to, the persistence ofthe virus, the genetic diversity of the virus during replication in thehost, the high incident rate of the virus developing drug-resistantmutants, and the lack of reproducible infectious culture systems andsmall-animal models for HCV replication and pathogenesis. In a majorityof cases, given the mild course of the infection and the complex biologyof the liver, careful consideration must be given to antiviral drugs,which are likely to have significant side effects.

Due to the high degree of variability in the viral surface antigens,existence of multiple viral genotypes, and demonstrated specificity ofimmunity, the development of a successful vaccine in the near future isunlikely. Only two approved therapies for HCV infection are currentlyavailable. The original treatment regimen generally involves a 3-12month course of intravenous interferon-α (IFN-α), while a new approvedsecond-generation treatment involves co-treatment with IFN-α and thegeneral antiviral nucleoside mimics like ribavirin. Both of thesetreatments suffer from interferon related side effects as well as lowefficacy against HCV infections. There exists a need for the developmentof effective antiviral agents for treatment of HCV infection due to thepoor tolerability and disappointing efficacy of existing therapies.

Cyclosporin A (CsA), a neutral cyclic undecapeptide isolated from thefungus Tolypocladium injlaturn and currently marketed as Neoral andsandimmune (Novartis, Basel, Switzerland), has been widely used for theprevention of organ transplant rejection. The molecular basis for theimmunosuppressant activity of cyclosporin A and cyclosporin analoguesbegins with the passive diffusion of the cyclosporin (Cs) molecule intothe cell, followed by binding to its intracellular receptor, cyclophilinA (CypA). CypA belongs to a family of proteins that catalyze cis-transpeptidyl-prolyl isomerization, i.e., PPIase, a rate-limiting step inprotein folding. CsA and other cyclosporin analogues bind to the activesite of CypA. However, immunosuppression is not believed to be due tothe inhibition of CypA PPIase activity. The target of the CsA-CypAcomplex is a Ca²⁺-calmodulin-dependent serine-threonine-specific proteinphosphatase, calcineurin. In T-cells responding to antigen presentation,an increase in intracellular Ca²⁺ activates calcineurin, whichsubsequently dephosphorylates the transcription factor called thenuclear factor of activated T-cells (“NFAT”). Dephosphorylated NFATundergoes a molecular change, e.g., homodimerization that allows it tocross into the nucleus, and promotes the expression of T-cell activationgenes. CsA and other immunosuppressive cyclosporin derivatives inhibitcalcineurin which results in the inhibition of expression of cytokinegenes, e.g., interleukin-2 (IL-2) that promotes T-cell activation andproliferation, i.e., immunosuppressive activity.

Since the original discovery of CsA, a wide variety of naturallyoccurring cyclosporins have been isolated and identified, and manyfurther nonnatural cyclosporins have been prepared by total- orsemi-synthetic means or by the application of modified culturetechniques. The class comprised by the cyclosporins is thus nowsubstantial and includes, for example, the naturally occurringcyclosporins A through Z [cf., Traber et al.; 1, Helv. Chim. Acta, 60,1247-1255 (1977); Traber et al.; 2, Helv. Chim. Acta, 65, 1655-1667(1982); Kobel et al.; Europ. J. Applied Microbiology and Biotechnology,14, 273-240 (1982); and von Wartburg et al.; Progress in Allergy, 38,28-45 (1986)], as well as various non-natural cyclosporin derivativesand artificial or synthetic cyclosporin derivatives and artificial orsynthetic cyclosporins including dihydrocyclosporins [in which the-MeBmt-residue is saturated by hydrogenation]; derivatized cyclosporins(e.g., in which the 3′-O-atom of the -MeBmt- residue is acylated or afurther substituent is introduced at the a-carbon atom of the sarcosylresidue at the 3-position); and cyclosporins in which variant aminoacids are incorporated at specific positions within the peptidesequence, e.g. employing the total synthetic method for the productionof cyclosporins developed by R. Wenger—see e.g. Traber et al., 1; Traberet al., 2; and Kobel et al., loc cit. U.S. Pat. Nos. 4,108,985,4,220,641, 4,288,431, 4,554,351, 4,396,542 and 4,798,823; EuropeanPatent Publication Nos. 34,567A, 56,782A, 300,784A and 300,785;International Patent Publication No. WO 86/02080 and UK PatentPublication Nos. 2,206,119 and 2,207,678; Wenger 1, Transpl. Proc., 15Suppl. 1:2230 (1983); Wenger 2, Angew. Chem. Int. Ed. 24, 77 (1985) andWenger 3, Progress in the Chemistry of Organic Natural Products, 50, 123(1986). Several synthetic modifications of the -MeBmt- residue residingat position 1 of the cyclosporin undecapeptide have been describedincluding: Park et al., Tetrahedron Lett. 1989, 30, 4215-4218; U.S. Pat.Nos. 5,239,037, 5,293,057; U.S. Publication Nos. US20020142946,US20030087813, and US20030104992 assigned to Enanta Pharmaceuticals,Inc.; PCT Publication Nos. WO99/18120 and WO03/033526 both assigned toIsotechnika; and U.S. Pat. Nos. 4,384,996, 4,771,122, 5,284,826, and5,525,590 assigned to Sandoz.

The compound cyclosporine (CsA) has found wide use since itsintroduction in the fields of organ transplantation andimmunomodulation, and has brought about a significant increase in thesuccess rate for transplantation procedures. Undesired side effectsassociated with cyclosporine, however, such as nephrotoxicity, have ledto a continued search for immunosuppressant compounds having improved,efficacy and safety.

CsA and certain derivatives have been reported as having anti-HCVactivity, see Watashi et al., Hepatology, 2003, Volume 38, pp 1282-1288,Nakagawa et al., Biochem. Biophys. Res. Commun. 2004, Volume 3 13, pp42-7, and Shimotohno and K. Watashi, 2004 American Transplant Congress,Abstract No. 648 (American Journal of Transplantation 2004, Volume 4,Issue s8, Pages 1-653). The authors of the Nakagawa et al. paper statethat certain chaperone activities, such as those of cyclophilins, may becrucial for the processing and maturation of the viralproteins and forviral replication. Cyclosporine derivatives having HCV activity areknown from International Publication Nos. WO2005/021028, WO2006/039668,WO2006/038088, WO 2006/039688, WO 2007/112352, WO 2007/112357, WO2007/112345 and WO 2007/041631.

A subsequent controlled clinical trial showed that a combination of CsAwith interferon α2b is more effective than interferon monotherapy,especially in patients with high viral loads (Inoue et al., “CombinedInterferon α2b nd Cyclosporin A in the Treatment of Chronic Hepatitis C:Controlled Trial,” J. Gastroenterol. 38:567-572 (2003).

PCT International Patent Publication No. WO 2006/005610 recentlydescribed the use of a combination of cyclosporin A and pegylatedinterferon for treating hepatitis C viral infection. In addition, PCTInternational Patent Publication No. WO 2005/021028 relates to the useof non-immunosuppressive cyclosporine for treatment of HCV disorders.Also, Paeshuyse et al., “Potent and Selective Inhibition of Hepatitis CVirus Replication by the Non-Immunosuppressive Cyclosporin AnalogueDEBIO-025,” Antiviral Research 65(3):A41 (2005) recently publishedresults for a non-immunosuppressive cyclosporin analogue, DEBIO-025,that exhibited potent and selective inhibition of hepatitis C virusreplication. Debio-025 does possess potent binding affinity forcyclophilin A.

NS5A is a membrane-anchored phosphoprotein that is observed in basallyphosphorylated (56 kDa) and hyperphosphorylated (58 kDa) forms. Whileits function has not fully been elucidated, NS5A is believed to beimportant in viral replication. The HCV NS5A protein is described, forexample, in Tan, S.-L., Katzel, M. G. Virology, 284, 1(2001); and inRice, C. M. Nature, 435, 374(2005). A general strategy for thedevelopment of antiviral agents is to inactivate virally encodedproteins, including NS5A, that are essential for the replication of thevirus. The relevant patent disclosures describing the synthesis of HCVNS5A inhibitors are: US 2009/0202478; US 2009/0202483; WO 2009/020828;WO 2009/020825; WO 2009/102318; WO 2009/102325; Wo 2009/102694; WO2008/144380; WO 2008/021927; WO 2008/021928; WO 2008/021936; WO2006/1333262; WO 2004/014852; WO 2008/070447; WO 2009/034390; WO2006/079833; WO 2007/031791; WO 2007/070556; WO 2007/070600; WO2008/064218; WO 2008/154601; WO 2007/082554; WO 2008/048589, thecontents of each of which are expressly incorporated by referenceherein.

SUMMARY OF THE INVENTION

The present invention relates to novel antiviral compounds representedherein below, pharmaceutical compositions comprising such compounds, andmethods for the treatment or prophylaxis of viral (particularly HCV)infection in a subject in need of such therapy with said compounds.Compounds of the present invention interfere with the life cycle of thehepatitis C virus and are also useful as antiviral agents.

In its principal embodiment, the present invention provides a compoundof formula (I),

or a pharmaceutically acceptable salt, ester or prodrug thereof, where:

-   Ring A and ring B are each independently selected from:    -   a) Phenyl;    -   b) Substituted phenyl;    -   c) Six membered heteroaryl containing one, two or three nitrogen        atoms;    -   d) Substituted six membered heteroaryl containing one, two or        three nitrogen atoms;-   R₁ and R₂ are each independently selected from:    -   a) Hydrogen;    -   b) Deuterium;    -   c) Halogen;    -   d) R₁₁, where is selected from:        -   1) C₁-C₁₂ alkyl;        -   2) Substituted C₁-C₁₂ alkyl;        -   3) C₂-C₁₂ alkenyl;        -   4) Substituted C₂-C₁₂ alkenyl;        -   5) C₂-C₁₂ alkynyl;        -   6) Substituted C₂-C₁₂ alkynyl;        -   7) C₃-C₁₂ cycloalkyl;        -   8) Substituted C₃-C₁₂ cycloalkyl;        -   9) Aryl;        -   10) Substituted aryl;        -   11) Heterocycloalkyl;        -   12) Substituted heterocycloalkyl;        -   13) Heteroaryl; or        -   14) Substituted heteroaryl;    -   e) —C(O)OR₁₂, where R₁₂ is selected from hydrogen or R₁₁ where        R₁₁ as previously defined;    -   f) —C(O)R₁₂, where R₁₂ is as previously defined;    -   g) —C(O)N(R₁₃)(R₁₄), where R₁₃ and R₁₄ are independently        selected from R₁₂ and R₁₂ is as previously defined or R₁₃ and        R₁₄, together with the nitrogen atom to which they are attached,        form a substituted or unsubstituted heterocycloalkyl;    -   h) —C(O)SR₁₂, where R₁₂ is as previously defined;    -   i) —C(S)OR₁₂, where R₁₂ is as previously defined;    -   j) —C(S)SR₁₂, where R₁₂ is as previously defined;    -   k) —OR₁₂, where R₁₂ is as previously defined;    -   l) —SR₁₂, where R₁₂ is as previously defined;    -   m) —NR₁₃R₁₄, where R₁₃ and R₁₄ are as previously defined;-   R₃, R₄, R₅ and R₆ are independently selected from:    -   a) Hydrogen;    -   b) Deuterium;    -   c) C₁-C₁₂ alkyl;    -   d) Substituted C₁-C₁₂ alkyl;    -   e) C₂-C₁₂ alkenyl;    -   f) Substituted C₂-C₁₂ alkenyl;    -   g) C₂-C₁₂ alkynyl;    -   h) Substituted C₂-C₁₂ alkynyl;    -   i) C₃-C₁₂ cycloalkyl;    -   j) Substituted C₃-C₁₂ cycloalkyl;    -   k) Aryl;    -   l) Substituted aryl;    -   m) Heterocycloalkyl;    -   n) Substituted heterocycloalkyl;    -   o) Heteroaryl; or    -   p) Substituted heteroaryl;-   or-   R₃ and R₅, together with the nitrogen atom and the carbon atom to    which they are attached, and/or R₄ and R₆, together with the    nitrogen atom and the carbon atom to which they are attached,    independently form a substituted or unsubstituted heterocycloalkyl;-   R^(a) and R^(b) are independently selected from:    -   a) Hydrogen;    -   b) R₁₁;    -   c) —C(O)O—R₁₁, where R₁₁ is as previously defined;    -   d) —C(O)NHR₁₁, where R₁₁ is as previously defined;    -   or R^(a) and R^(b), together with the nitrogen atom to which        they are attached, form a substituted or unsubstituted        heterocycloalkyl;-   R₇ is selected from:    -   a) R₁₁, where R₁₁ is as previously defined;    -   b) —OR₁₁, where R₁₁ is as previously defined;    -   c) —SR₁₁, where R₁₁ is as previously defined; and    -   d) —NR₁₃R₁₄, where R₁₃ and R₁₄ are as previously defined;-   D and E are each independently selected from:    -   a) C₁-C₁₂ alkylene containing 0, 1, 2 or 3 heteroatoms        independently selected from O, S and N;    -   b) Substituted C₁-C₁₂ alkylene containing 0, 1, 2 or 3        heteroatoms independently selected from O, S and N;    -   c) C₂-C₁₂ alkenylene containing 0, 1, 2 or 3 heteroatoms        independently selected from O, S and N;    -   d) Substituted C₂-C₁₂ alkenylene containing 0, 1, 2 or 3        heteroatoms independently selected from O, S and N;    -   e) C₂-C₁₂ alkynylene containing 0, 1, 2 or 3 heteroatoms        independently selected from O, S and N;    -   f) Substituted C₂-C₁₂ alkynylene containing 0, 1, 2 or 3        heteroatoms independently selected from O, S and N;    -   g) C₃-C₁₂ cycloalkylene;    -   h) Substituted C₃-C₁₂ cycloalkylene;    -   i) Heterocycloalkylene; and    -   j) Substituted heterocycloalkylene;-   L is absent, or selected from:    -   a) —O—;    -   b) —N(R₁₂)—; where R₁₂ is as previously defined;    -   c) —N(C(O)R₁₁)—, where R₁₁ is as previously defined;    -   d) —N(C(O)OR₁₁)—, where R₁₁ is as previously defined;    -   e) —S(O)_(m)—, where m=0, 1, or 2;    -   f) —OC(O)NH—;    -   g) —OC(S)NH—;    -   h) —SC(S)NH—;    -   i) —NHC(O)NH—;    -   j) —NHC(S)NH—;    -   k) —O-M-, where M is selected from optionally substituted C₁-C₁₂        alkylene, or optionally substituted C₂-C₁₂ alkenylene, or        optionally substituted C₂-C₁₂ alkynylene, or optionally        substituted C₃-C₁₂ cycloalkylene;    -   l) —S(O)_(m)-M-, where m=0, or 1, or 2 and M is as previously        defined;    -   m) —OC(O)NH-M-, where M is as previously defined;    -   n) —OC(S)NH-M-, where M is as previously defined;    -   o) —NHC(O)NH-M-, where M is as previously defined; and    -   p) —NHC(S)NH-M-, where M is as previously defined;-   J is R₁₁, where R₁₁ is as previously defined;-   K is ethyl, 1-hydroxyethyl, isopropyl or n-propyl;-   R₈ is selected from:    -   a) Hydrogen;    -   b) C₁-C₁₂ alkyl; and    -   c) Substituted C₁-C₁₂ alkyl;-   R^(c) is methyl, ethyl, allyl or n-propyl; and-   R₉ is hydrogen or R₁₁, where R₁₁ is as previously defined.

In embodiments in which R₃ and R₅, together with the nitrogen atom andthe carbon atom which they are attached, and/or R₄ and R₆, together withthe nitrogen atom and the carbon atom to which they are attached, form asubstituted or unsubstituted heterocycloalkyl, suitable substituted orunsubstituted heterocycloalkyls include, but are not limited to:

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor combination of compounds of the present invention, or apharmaceutically acceptable salt form, prodrug, salt of a prodrug,stereoisomer, tautomer, solvate, or combination thereof, in combinationwith a pharmaceutically acceptable carrier or excipient.

In still another embodiment, the present invention provides a method ofinhibiting the replication of an RNA-containing virus comprisingcontacting said virus with a therapeutically effective amount of acompound or a combination of compounds of the present invention, or apharmaceutically acceptable salt, prodrug, salt of a pro drug,stereoisomer, tautomer, solvate, or combination thereof. Particularly,this invention is directed to methods of inhibiting the replication ofhepatitis C virus.

Yet another embodiment, the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising administering to a patient in need of such treatment atherapeutically effective amount of a compound or combination ofcompounds of the present invention, or a pharmaceutically acceptablesalt form, prodrug, salt of a prodrug, stereoisomer, or tautomer,solvate, or combination thereof. Particularly, this invention isdirected to methods of treating or preventing infection caused byhepatitis C virus.

Yet another embodiment of the present invention provides the use of acompound or combination of compounds of the present invention, or atherapeutically acceptable salt form, prodrug, salt of a prodrug,stereoisomer or tautomer, solvate, or combination thereof, as definedhereinafter, in the preparation of a medicament for the treatment orprevention of infection caused by RNA-containing virus, specificallyhepatitis C virus (HCV).

DETAILED DESCRIPTION OF THE INVENTION

In a first embodiment of the present invention is a compound of formula(I) as illustrated above, or a pharmaceutically acceptable salt, esteror prodrug thereof.

Representative subgenera of the present invention include:

Compounds of formula (I) which are represented by the formula (II),

wherein R₃, R₄, R₅, R₆, R₇, R₈, R^(a), R^(b), E, L, and D are as definedin formula (I).

Compounds of formula (I) which are represented by the formula (III),

wherein, R₇, R₈, R^(a), R^(b), E, L, and D are as defined in formula(I);

Compounds of formula (I) which are represented by the formula (IV),

wherein R₇, R₈, E, L, and D are as defined in formula (I).

Representative compounds of the present invention are those of formula(V) or (VI):

wherein:

L′ is selected from: —N(Me)-; —NH—; —N(Boc)-; —N(Ac)—; —OC(O)NH—,—SCH₂CH₂OC(O)NH—, and —OCH₂CH₂OC(O)NH—;

n is 0, 1, 2, 3, 4 or 5; and

R₇C(O)— is selected from the following table:

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A further embodiment of the present invention includes pharmaceuticalcompositions comprising any single compound delineated herein, or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof,with a pharmaceutically acceptable carrier or excipient.

Yet another embodiment of the present invention is a pharmaceuticalcomposition comprising a combination of two or more compounds delineatedherein, or a pharmaceutically acceptable salt, ester, solvate, orprodrug thereof, with a pharmaceutically acceptable carrier orexcipient.

Furthermore, the compounds of the invention are useful for the treatmentand prevention of hepatic disease such as immunogenic diseases (forexample, chronic autoimmune liver diseases such as the group consistingof autoimmune hepatitis, primary biliary cirrhosis and sclerosingcholangitis), partial liver resection, acute liver necrosis (e.g.,necrosis caused by toxin, viral hepatitis, shock or anoxia), B-virushepatitis, non-A/non-B hepatitis, cirrhosis (such as alcoholiccirrhosis) and hepatic failure such as fulminant hepatic failure,late-onset hepatic failure and “acute-onchronic” liver failure (acuteliver failure on chronic liver diseases), and moreover are useful forvarious diseases because of their useful activity such as augmention ofchemotherapeutic effect, preventing or treating activity ofcytomegalovirus infection, particularly human cytomegalovirus (HCMV)infection, anti-inflammatory activity, and so on.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound delineated herein incombination with one or more HCV compounds known in the art, or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof,with a pharmaceutically acceptable carrier or excipient.

It will be appreciated that reference herein to therapy and/or treatmentincludes, but is not limited to prevention, retardation, prophylaxis,therapy and cure of the disease. It will further be appreciated thatreferences herein to treatment or prophylaxis of HCV infection includestreatment or prophylaxis of HCV-associated disease such as liverfibrosis, cirrhosis and hepatocellular carcinoma.

It will be further appreciated that the compounds of the presentinvention may contain one or more asymmetric carbon atoms and may existin racemic, diastereoisomeric, and optically active forms. It will stillbe appreciated that certain compounds of the present invention may existin different tautomeric forms. All tautomers are contemplated to bewithin the scope of the present invention.

It will be further appreciated that the compounds of the invention, ortheir pharmaceutically acceptable salts, stereoisomers, tautomers,prodrugs or salt of a prodrug thereof, can be administered as the soleactive pharmaceutical agent, or used in combination with one or moreagents to treat or prevent hepatitis C infections or the symptomsassociated with HCV infection. Other agents to be administered incombination with a compound or combination of compounds of the inventioninclude therapies for disease caused by HCV infection that suppressesHCV viral replication by direct or indirect mechanisms. These includeagents such as host immune modulators (for example, interferon-alpha,pegylated interferon-alpha, interferon-beta, interferon-gamma, CpGoligonucleotides and the like), or antiviral compounds that inhibit hostcellular functions such as inosine monophosphate dehydrogenase (forexample, ribavirin and the like). Also included are cytokines thatmodulate immune function. Also included are vaccines which comprise HCVantigens or antigen adjuvant combinations directed against HCV. Alsoincluded are agents that interact with host cellular components to blockviral protein synthesis by inhibiting the internal ribosome entry site(IRES) initiated translation step of HCV viral replication or to blockviral particle maturation and release with agents targeted toward theviroporin family of membrane proteins such as, for example, HCV P7 andthe like. Other agents to be administered in combination with a compoundof the present invention include any agent or combination of agents thatinhibit the replication of HCV by targeting proteins of the viral genomeinvolved in the viral replication. These agents include but are notlimited to other inhibitors of HCV RNA dependent RNA polymerase such as,for example, nucleoside type polymerase inhibitors described inWO01/90121(A2), or U.S. Pat. No. 6,348,587B1 or WO01/60315 or WO01/32153or non-nucleoside inhibitors such as, for example, benzimidazolepolymerase inhibitors described in EP 1 162 196 A1 or WO02/04425.

Accordingly, one aspect of the invention is directed to a method fortreating or preventing an infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents selected from the group consisting of a host immunemodulator and a second antiviral agent, or a combination thereof, with atherapeutically effective amount of a compound or combination ofcompounds of the invention, or a pharmaceutically acceptable salt,stereoisomer, tautomer, prodrug, salt of a prodrug, or combinationthereof. Examples of the host immune modulator are, but not limited to,interferon-alpha, pegylated-interferon-alpha, interferon-beta,interferon-gamrna, a cytokine, a vaccine, and a vaccine comprising anantigen and an adjuvant, and said second antiviral agent inhibitsreplication of HCV either by inhibiting host cellular functionsassociated with viral replication or by targeting proteins of the viralgenome.

Further aspect of the invention is directed to a method of treating orpreventing infection caused by an RNA-containing virus comprisingco-administering to a patient in need of such treatment an agent orcombination of agents that treat or alleviate symptoms of HCV infectionincluding cirrhosis and inflammation of the liver, with atherapeutically effective amount of a compound or combination ofcompounds of the invention, or a pharmaceutically acceptable salt,stereoisomer, tautomer, prodrug, salt of a prodrug, or combinationthereof. Yet another aspect of the invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by hepatitis B(HBV) infection, with a therapeutically effective amount of a compoundor a combination of compounds of the invention, or a pharmaceuticallyacceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, orcombination thereof. An agent that treats patients for disease caused byhepatitis B (HBV) infection may be for example, but not limited thereto,L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combinationthereof. Example of the RNA-containing virus includes, but not limitedto, hepatitis C virus (HCV).

Another aspect of the invention provides a method of treating orpreventing infection caused by an RNA-containing virus comprisingco-administering to a patient in need of such treatment one or moreagents that treat patients for disease caused by human immunodeficiencyvirus (HIV) infection, with a therapeutically effective amount of acompound or a combination of compounds of the invention, or apharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, saltof a prodrug, or combination thereof. The agent that treats patients fordisease caused by human immunodeficiency virus (HIV) infection mayinclude, but is not limited thereto, ritonavir, lopinavir, indinavir,nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114,fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir,zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125,L-870812, S-1360, enfuvirtide (T-20) or T-1249, or any combinationthereof. Example of the RNA-containing virus includes, but not limitedto, hepatitis C virus (HCV). In addition, the present invention providesthe use of a compound or a combination of compounds of the invention, ora therapeutically acceptable salt form, stereoisomer, or tautomer,prodrug, salt of a prodrug, or combination thereof, and one or moreagents selected from the group consisting of a host immune modulator anda second antiviral agent, or a combination thereof, to prepare amedicament for the treatment of an infection caused by an RNA-containingvirus in a patient, particularly hepatitis C virus. Examples of the hostimmune modulator are, but not limited to, interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, acytokine, a vaccine, and a vaccine comprising an antigen and anadjuvant, and said second antiviral agent inhibits replication of HCVeither by inhibiting host cellular functions associated with viralreplication or by targeting proteins of the viral genome.

When used in the above or other treatments, combination of compound orcompounds of the invention, together with one or more agents as definedherein above, can be employed in pure form or, where such forms exist,in pharmaceutically acceptable salt form, prodrug, salt of a prodrug, orcombination thereof. Alternatively, such combination of therapeuticagents can be administered as a pharmaceutical composition containing atherapeutically effective amount of the compound or combination ofcompounds of interest, or their pharmaceutically acceptable salt form,prodrugs, or salts of the prodrug, in combination with one or moreagents as defined hereinabove, and a pharmaceutically acceptablecarrier. Such pharmaceutical compositions can be used for inhibiting thereplication of an RNA-containing virus, particularly Hepatitis C virus(HCV), by contacting said virus with said pharmaceutical composition. Inaddition, such compositions are useful for the treatment or preventionof an infection caused by an RNA-containing virus, particularlyHepatitis C virus (HCV).

Hence, further aspect of the invention is directed to a method oftreating or preventing infection caused by an RNA-containing virus,particularly a hepatitis C virus (HCV), comprising administering to apatient in need of such treatment a pharmaceutical compositioncomprising a compound or combination of compounds of the invention or apharmaceutically acceptable salt, stereoisomer, or tautomer, prodrug,salt of a prodrug, or combination thereof, one or more agents as definedhereinabove, and a pharmaceutically acceptable carrier.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time orwithin a predetermined period of time, or the therapeutic agents can begiven as a single unit dosage form.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a mammal, including butnot limited to agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina mammal. Such agents can be selected from another anti-HCV agent; anHIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other anti-HCV agents include those agents that are effective fordiminishing or preventing the progression of hepatitis C relatedsymptoms or disease. Such agents include but are not limited toimmunomodulatory agents, inhibitors of HCV NS3 protease, otherinhibitors of HCV polymerase, inhibitors of another target in the HCVlife cycle and other anti-HCV agents, including but not limited toribavirin, amantadine, levovirin and viramidine.

Immunomodulatory agents include those agents (compounds or biologicals)that are effective to enhance or potentiate the immune system responsein a mammal. Immunomodulatory agents include, but are not limited to,inosine monophosphate dehydrogenase inhibitors such as VX-497(merimepodib, Vertex Pharmaceuticals), class I interferons, class IIinterferons, consensus interferons, asialo-interferons pegylatedinterferons and conjugated interferons, including but not limited tointerferons conjugated with other proteins including but not limited tohuman albumin. Class I interferons are a group of interferons that allbind to receptor type I, including both naturally and syntheticallyproduced class I interferons, while class II interferons all bind toreceptor type II. Examples of class I interferons include, but are notlimited to, [alpha]-, [beta]-, [delta]-, [omega]-, and[tau]-interferons, while examples of class II interferons include, butare not limited to, [gamma]-interferons.

Inhibitors of HCV NS3 protease include agents (compounds or biologicals)that are effective to inhibit the function of HCV NS3 protease in amammal. Inhibitors of HCV NS3 protease include, but are not limited to,those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO2004/101605, WO 2004/103996, WO 2005/028501, WO 2005/070955, WO2006/000085, WO 2006/007700 and WO 2006/007708 (all by BoehringerIngelheim), WO 02/060926, WO 03/053349, WO03/099274, WO 03/099316, WO2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO2005/051410, WO 2005/054430 (all by BMS), WO 2004/072243, WO2004/093798, WO 2004/113365, WO 2005/010029 (all by Enanta), WO2005/037214 (Intermune) and WO 2005/051980 (Schering), and thecandidates identified as VX-950, ITMN-191 and SCH 503034.

Inhibitors of HCV polymerase include agents (compounds or biologicals)that are effective to inhibit the function of an HCV polymerase. Suchinhibitors include, but are not limited to, non-nucleoside andnucleoside inhibitors of HCV NS5B polymerase. Examples of inhibitors ofHCV polymerase include but are not limited to those compounds describedin: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141, WO2004/064925, WO 2004/065367, WO 2005/080388 and WO 2006/007693 (all byBoehringer Ingelheim), WO 2005/049622 (Japan Tobacco), WO 2005/014543(Japan Tobacco), WO 2005/012288 (Genelabs), WO 2004/087714 (IRBM), WO03/101993 (Neogenesis), WO 03/026587 (BMS), WO 03/000254 (JapanTobacco), and WO 01/47883 (Japan Tobacco), and the clinical candidatesXTL-2125, HCV 796, R-1626 and NM 283.

Inhibitors of another target in the HCV life cycle include agents(compounds or biologicals) that are effective to inhibit the formationand/or replication of HCV other than by inhibiting the function of theHCV NS3 protease. Such agents may interfere with either host or HCVviral mechanisms necessary for the formation and/or replication of HCV.Inhibitors of another target in the HCV life cycle include, but are notlimited to, entry inhibitors, agents that inhibit a target selected froma helicase, a NS2/3 protease and an internal ribosome entry site (IRES)and agents that interfere with the function of other viral targetsincluding but not limited to an NS5A protein and an NS4B protein.

It can occur that a patient may be co-infected with hepatitis C virusand one or more other viruses, including but not limited to humanimmunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis Bvirus (HBV). Thus also contemplated is combination therapy to treat suchco-infections by co-administering a compound according to the presentinvention with at least one of an HIV inhibitor, an HAV inhibitor and anHBV inhibitor.

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, an idenyl. An aryl group can be amonovalent, bivalent or higher valent radical, as required by thecontext in which the term is used.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbon, wherein any N or S containedwithin the ring may be optionally oxidized. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzooxazolyl, quinoxalinyl. A heteroaryl group can be a monovalent,bivalent or higher valent radical, as required by the context in whichthe term is used.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

The terms “C₁-C₁₂ alkyl,” as used herein, refer to saturated, straight-or branched-chain hydrocarbon radicals containing between one and twelvecarbon atoms, which can be optionally inserted one or more hetero atomssuch as, but not limited to O, N and S. Examples of C₁-C₁₂ alkylradicals include, but are not limited to, ethyl, propyl, isopropyl,n-hexyl, octyl, decyl, dodecyl radicals, —CH₂OCH₃, —CH₂SCH₃,—CH₂OCH₂CH₃, —CH(CH₃)OCH₂CH₂CH₂CH₃.

The terms “C₁-C₁₂ alkylene,” as used herein, refer to saturated,straight- or branched-chain hydrocarbon biradicals containing betweenone and twelve carbon atoms, which can be optionally inserted one ormore hetero atoms such as, but not limited to O, N and S. Examples ofC₁-C₁₂ alkyl radicals include, but are not limited to, ethylene,propylene, isopropylene, n-hexylene, octylene, decylene, —CH₂OCH₂—,—CH₂SCH₂—, —CH₂OCH₂CH₂—, —CH(CH₃)OCH₂CH₂CH₂CH₂—.

The term “C₂-C₁₂ alkenyl,” as used herein, refer to straight- orbranched-chain hydrocarbon radicals containing from two to twelve carbonatoms having at least one carbon-carbon double bond. One or more heteroatoms such as, but not limited to O, N and S can be optionally insertedbetween the carbon atoms, provided the hetero atoms are not next to thedouble bond carbons. Alkenyl groups include, but are not limited to, forexample, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl,octenyl, —CH(CH₃)OCH₂CH═CH₂, and the like.

The term “C₂-C₁₂ alkenylene,” as used herein, refer to straight- orbranched-chain hydrocarbon biradicals containing from two to twelvecarbon atoms having at least one carbon-carbon double bond. One or morehetero atoms such as, but not limited to O, N and S can be optionallyinserted between the carbon atoms, provided the hetero atoms are notnext to the double bond carbons. Alkenylene groups include, but are notlimited to, for example, 1, —CH═CH—, —CH₂CH═CH—, —CH₂CH═CHCH₂—,—CH₂C(CH₃)═CH—, —CH(CH₃)OCH₂CH═CH₂, and the like.

The term “C₂-C₁₂ alkynyl,” as used herein, refer to straight- orbranched-chain hydrocarbon radicals containing from two to twelve carbonatoms having at least one carbon-carbon triple bond. One or more heteroatoms such as, but not limited to O, N and S can be optionally insertedbetween the carbon atoms, provided the hetero atoms are not next to thetriple bond carbons. Representative alkynyl groups include, but are notlimited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl,octynyl, —CH(CH₃)OCH₂C≡CH and the like.

The term “C₂-C₁₂ alkynylene,” as used herein, refer to straight- orbranched-chain hydrocarbon biradicals containing from two to twelvecarbon atoms having at least one carbon-carbon triple bond. One or morehetero atoms such as, but not limited to O, N and S can be optionallyinserted between the carbon atoms, provided the hetero atoms are notnext to the triple bond carbons. Representative alkynyl groups include,but are not limited to, for example, ethynylene, 1-propynylene,1-butynylene, heptynylene, octynylene, —CH(CH₃)OCH₂C≡C— and the like.

The term “C₃-C₁₂-cycloalkyl,” as used herein, refers to a monocyclic orpolycyclic saturated carbocyclic ring compound. Examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; and examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

The term “C₃-C₁₂-cycloalkylene,” as used herein, refers to a monocyclicor polycyclic saturated carbocyclic ring compound. Examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropylene,cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene andcyclooctylene, bicyclo[2.2.1]heptylene, and bicyclo[2.2.2]octylene.

The term “C₃-C₁₂ cycloalkenyl” as used herein, refers to monocyclic orpolycyclic carbocyclic ring compound having at least one carbon-carbondouble bond. Examples of C₃-C₁₂ cycloalkenyl include, but not limitedto, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and the like.

The term “C₃-C₁₂ cycloalkenylene” as used herein, refers to monocyclicor polycyclic carbocyclic ring compound having at least onecarbon-carbon double bond. Examples of C₃-C₁₂ cycloalkenylene include,but not limited to, cyclopropenylene, cyclobutenylene, cyclopentenylene,cyclohexenylene, cycloheptenylene, cyclooctenylene, and the like.

It is understood that any alkyl, alkenyl, alkynyl and cycloalkyl moietydescribed herein can also be an aliphatic group, an alicyclic group or aheterocyclic group. An “aliphatic” group is a non-aromatic moiety thatmay contain any combination of carbon atoms, hydrogen atoms, halogenatoms, oxygen, nitrogen or other atoms, and optionally contain one ormore units of unsaturation, e.g., double and/or triple bonds. Analiphatic group may be straight chained, branched or cyclic andpreferably contains between about 1 and about 24 carbon atoms, moretypically between about 1 and about 12 carbon atoms. In addition toaliphatic hydrocarbon groups, aliphatic groups include, for example,polyalkoxyalkyls, such as polyalkylene glycols, polyamines, andpolyimines, for example. Such aliphatic groups may be furthersubstituted.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or bicyclic saturated carbocyclic ring compound by theremoval of a single hydrogen atom. Examples include, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl,and bicyclo[2.2.2]octyl. Such alicyclic groups may be furthersubstituted.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and referred to a non-aromatic ring or a bi- ortri-cyclic group fused system, where (i) each ring system contains atleast one heteroatom independently selected from oxygen, sulfur andnitrogen, (ii) each ring system can be saturated or unsaturated (iii)the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) thenitrogen heteroatom may optionally be quaternized, (v) any of the aboverings may be fused to an aromatic ring, and (vi) the remaining ringatoms are carbon atoms which may be optionally oxo-substituted.Representative heterocyclic groups include, but are not limited to,1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl,morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl,pyridazinonyl, and tetrahydrofuryl. Such heterocyclic groups may befurther substituted.

The term “substituted” refers to substitution by independent replacementof one, two, or three or more of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —CN, —N₃, —NH₂, protected amino, oxo, thioxo,—NH—C₁-C₁₂-alkyl, —NH—C₂-C₈-alkenyl, —NH—C₂-C₈-alkynyl,—NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH-heteroaryl, —NH-heterocycloalkyl,-dialkylamino, -diarylamino, -diheteroarylamino, —O—C₁-C₁₂-alkyl,—O—C₂-C₈-alkenyl, —O—C₂-C₈-alkynyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl,—O-heteroaryl, —O-heterocycloalkyl, —C(O)—C₁-C₁₂-alkyl,—C(O)—C₂-C₈-alkenyl, —C(O)—C₂-C₈-alkynyl, —C(O)—C₃-C₁₂-cycloalkyl,—C(O)-aryl, —C(O)-heteroaryl, —C(O)-heterocycloalkyl, —CONH₂,—CONH—C₁-C₁₂-alkyl, —CONH—C₂-C₈-alkenyl, —CONH—C₂-C₈-alkynyl,—CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl, —CONH-heteroaryl,—CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂—C₂-C₈-alkenyl,—OCO₂—C₂-C₈-alkenyl, —OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl,—OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —OCONH₂, —OCONH—C₁-C₁₂-alkyl,—OCONH—C₂-C₈-alkenyl, —OCONH—C₂-C₈-alkynyl, —OCONH—C₃-C₁₂-cycloalkyl,—OCONH-aryl, —OCONH-heteroaryl, —OCONH-heterocycloalkyl,—NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₈-alkenyl, —NHC(O)—C₂-C₈-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₈-alkenyl,—NHCO₂—C₂-C₈-alkynyl, —NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl,—NHCO₂-heteroaryl, —NHCO₂-heterocycloalkyl, —NHC(O)NH₂,—NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₈-alkenyl,—NHC(O)NH—C₂-C₈-alkynyl, —NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl,—NHC(O)NH-heteroaryl, —NHC(O)NH-heterocycloalkyl, NHC(S)NH₂,—NHC(S)NH—C₁-C₁₂-alkyl, —NHC(S)NH—C₂-C₈-alkenyl,—NHC(S)NH—C₂-C₈-alkynyl, —NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl,—NHC(S)NH-heteroaryl, —NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂,—NHC(NH)NH—C₁-C₁₂-alkyl, —NHC(NH)NH—C₂-C₈-alkenyl,—NHC(NH)NH—C₂-C₈-alkynyl, —NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl,—NHC(NH)NH-heteroaryl, —NHC(NH)NH-heterocycloalkyl,—NHC(NH)—C₁-C₁₂-alkyl, —NHC(NH)—C₂-C₈-alkenyl, —NHC(NH)—C₂-C₈-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₈-alkenyl, —C(NH)NH—C₂-C₈-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₈-alkenyl,—S(O)—C₂-C₈-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₈-alkenyl, —SO₂NH—C₂-C₈-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₈-alkenyl, —NHSO₂—C₂-C₈-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₈-alkenyl, —S—C₂-C₈-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthiomethyl. It is understood that the aryls, heteroaryls, alkyls,and the like can be further substituted.

The term “halogen,” as used herein, refers to an atom selected fromfluorine, chlorine, bromine and iodine.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reaction. Examples of hydroxyl activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxyl protecting groups for the present invention areacetyl (Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H₅), and trimethylsilyl(TMS or —Si(CH₃)₃).

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group”, as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, andthe like.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, NY, 1986.

The term “protic solvent’ as used herein, refers to a solvent that tendsto provide protons, such as an alcohol, for example, methanol, ethanol,propanol, isopropanol, butanol, t-butanol, and the like. Such solventsare well known to those skilled in the art, and it will be obvious tothose skilled in the art that individual solvents or mixtures thereofmay be preferred for specific compounds and reaction conditions,depending upon such factors as the solubility of reagents, reactivity ofreagents and preferred temperature ranges, for example. Furtherdiscussions of protogenic solvents may be found in organic chemistrytextbooks or in specialized monographs, for example: Organic SolventsPhysical Properties and Methods of Purification, 4th ed., edited by JohnA. Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, NY, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the Formula herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, 2^(nd) Ed. Wiley-VCH (1999); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject” as used herein refers to an animal. Preferably theanimal is a mammal. More preferably the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of thepresent invention. “Prodrug”, as used herein means a compound which isconvertible in vivo by metabolic means (e.g. by hydrolysis) to acompound of the invention. Various forms of prodrugs are known in theart, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs,Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4,Academic Press (1985); Krogsgaard-Larsen, et al., (ed). “Design andApplication of Prodrugs, Textbook of Drug Design and Development,Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug DeliverReviews, 8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); and Bernard Testa &Joachim Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

The present invention also relates to solvates of the compounds ofFormula (I), for example hydrates.

This invention also encompasses pharmaceutical compositions containing,and methods of treating viral infections through administering,pharmaceutically acceptable prodrugs of compounds of the invention. Forexample, compounds of the invention having free amino, amido, hydroxy orcarboxylic groups can be converted into prodrugs. Prodrugs includecompounds wherein an amino acid residue, or a polypeptide chain of twoor more (e.g., two, three or four) amino acid residues is covalentlyjoined through an amide or ester bond to a free amino, hydroxy orcarboxylic acid group of compounds of the invention. The amino acidresidues include but are not limited to the 20 naturally occurring aminoacids commonly designated by three letter symbols and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers or excipients.

As used herein, the term “pharmaceutically acceptable carrier orexcipient” means a non-toxic, inert solid, semi-solid or liquid filler,diluent, encapsulating material or formulation auxiliary of any type.Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as lactose, glucose and sucrose;starches such as corn starch and potato starch; cellulose and itsderivatives such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipientssuch as cocoa butter and suppository waxes; oils such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols such as propylene glycol; esters such as ethyloleate and ethyl laurate; agar; buffering agents such as magnesiumhydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffersolutions, as well as other non-toxic compatible lubricants such assodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions, may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

For pulmonary delivery, a therapeutic composition of the invention isformulated and administered to the patient in solid or liquidparticulate form by direct administration e.g., inhalation into therespiratory system. Solid or liquid particulate forms of the activecompound prepared for practicing the present invention include particlesof respirable size: that is, particles of a size sufficiently small topass through the mouth and larynx upon inhalation and into the bronchiand alveoli of the lungs. Delivery of aerosolized therapeutics,particularly aerosolized antibiotics, is known in the art (see, forexample U.S. Pat. No. 5,767,068 to VanDevanter et al., U.S. Pat. No.5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of whichare incorporated herein by reference). A discussion of pulmonarydelivery of antibiotics is also found in U.S. Pat. No. 6,014,969,incorporated herein by reference.

According to the methods of treatment of the present invention, viralinfections, conditions are treated or prevented in a patient such as ahuman or another animal by administering to the patient atherapeutically effective amount of a compound of the invention, in suchamounts and for such time as is necessary to achieve the desired result.

By a “therapeutically effective amount” of a compound of the inventionis meant an amount of the compound which confers a therapeutic effect onthe treated subject, at a reasonable benefit/risk ratio applicable toany medical treatment. The therapeutic effect may be objective (i.e.,measurable by some test or marker) or subjective (i.e., subject gives anindication of or feels an effect). An effective amount of the compounddescribed above may range from about 0.1 mg/Kg to about 500 mg/Kg,preferably from about 1 to about 50 mg/Kg. Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the activity of the specific compound employed; the specific compositionemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration, route of administration, and rateof excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or contemporaneously with thespecific compound employed; and like factors well known in the medicalarts.

The total daily dose of the compounds of this invention administered toa human or other animal in single or in divided doses can be in amounts,for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1to 25 mg/kg body weight. Single dose compositions may contain suchamounts or submultiples thereof to make up the daily dose. In general,treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

The compounds of the Formula described herein can, for example, beadministered by injection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.1 toabout 500 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositions ofthis invention will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with pharmaceutically exipients or carriers toproduce a single dosage form will vary depending upon the host treatedand the particular mode of administration. A typical preparation willcontain from about 5% to about 95% active compound (w/w). Alternatively,such preparations may contain from about 20% to about 80% activecompound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

When the compositions of this invention comprise a combination of acompound of the invention described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds of this invention. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds of thisinvention in a single composition.

The said “additional therapeutic or prophylactic agents” includes butnot limited to, immune therapies (eg. interferon), therapeutic vaccines,antifibrotic agents, anti-inflammatory agents such as corticosteroids orNSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines(e.g. theophylline), mucolytic agents, anti-muscarinics,anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists),anti-oxidants (eg N-acetylcysteine), cytokine agonists, cytokineantagonists, lung surfactants and/or antimicrobial and anti-viral agents(eg ribavirin and amantidine). The compositions according to theinvention may also be used in combination with gene replacement therapy.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one of ordinary skill in theart. All publications, patents, published patent applications, and otherreferences mentioned herein are hereby incorporated by reference intheir entirety.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are:

-   -   Ac for acetyl;    -   Boc₂O for di-tert-butyl-dicarbonate;    -   Boc for t-butoxycarbonyl;    -   Bz for benzoyl;    -   Bn for benzyl;    -   BocNHOH for tent-butyl N-hydroxycarbamate;    -   t-BuOK for potassium tert-butoxide;    -   BOP for (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium;    -   Hexafluorophosphate;    -   Brine for sodium chloride solution in water;    -   Cbz for benzyloxycarbonyl;    -   CDI for carbonyldiimidazole;    -   CH₂Cl₂ for dichloromethane;    -   CH₃ for methyl;    -   CH₃CN for acetonitrile;    -   Cs₂CO₃ for cesium carbonate;    -   dba for dibenzylidene acetone;    -   dppb for diphenylphosphino butane;    -   dppe for diphenylphosphino ethane;    -   DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene;    -   DCC for N,N′-dicyclohexylcarbodiimide;    -   DEAD for diethylazodicarboxylate;    -   DIAD for diisopropyl azodicarboxylate;    -   DIPEA or (i-Pr)₂EtN for N,N,-diisopropylethyl amine;    -   Dess-Martin periodinane for        1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one;    -   DMAP for 4-dimethylaminopyridine;    -   DME for 1,2-dimethoxyethane;    -   DMF for N,N-dimethylformamide;    -   DMSO for dimethyl sulfoxide;    -   DPPA for diphenylphosphoryl azide;    -   EDC for N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide;    -   EDC HCl for N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide        hydrochloride;    -   EtOAc for ethyl acetate;    -   EtOH for ethanol;    -   Et₂O for diethyl ether;    -   HATU for        O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium;    -   Hexafluorophosphate;    -   HCl for hydrogen chloride;    -   HOBT for 1-hydroxybenzotriazole;    -   K₂CO₃ for potassium carbonate;    -   MeOH for methanol;    -   Ms for mesyl or —SO₂—CH₃;    -   Ms₂O for methanesulfonic anhydride or mesyl-anhydride;    -   NaHCO₃ for sodium bicarbonate or sodium hydrogen carbonate;    -   Na₂CO₃ sodium carbonate;    -   NaOH for sodium hydroxide;    -   Na₂SO₄ for sodium sulfate;    -   NaHSO₃ for sodium bisulfate or sodium hydrogen sulfite;    -   Na₂S₂O₃ for sodium thiosulfate;    -   NH₂NH₂ for hydrazine;    -   NH₄HCO₃ for ammonium bicarbonate;    -   NH₄Cl for ammonium chloride;    -   NMMO for N-methylmorpholine N-oxide;    -   NaIO₄ for sodium periodate;    -   OH for hydroxy;    -   OsO₄ for osmium tetroxide;    -   TEA or Et₃N for triethylamine;    -   TFA for trifluoroacetic acid;    -   THF for tetrahydrofuran;    -   TPP or PPh₃ for triphenylphosphine;    -   Ts for tosyl or —SO₂—C₆H₄CH₃;    -   Ts₂O for tolylsulfonic anhydride or tosyl-anhydride;    -   TsOH for p-tolylsulfonic acid;    -   Pd for palladium;    -   Ph for phenyl;    -   Pd₂(dba)₃ for tris(dibenzylideneacetone) dipalladium (0);    -   Pd(PPh₃)₄ for tetrakis(triphenylphosphine)palladium (0);    -   TBS for tent-butyl dimethylsilyl;    -   TMS for trimethylsilyl;    -   TMSCl for trimethylsilyl chloride; or    -   CsA for cyclosporine A.        Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared.

As shown in Scheme 1, an intermediate of formula (1-3) was prepared byselective removal of amino acid in position four —N-methyl leucine ofcyclosporine A (see Roland Wenger et al, “Synthetic routes toNEtXaa⁴-cycloporin A derivatives as potential anti-HIV I drugs”,Tetrahedron Letters, 2000, 41, 7193, which is hereby incorporated byreference in its entirety). Thus, cyclosporine A was reacted with aceticanhydride, optionally in the presence of pyridine or DMAP in CH₂Cl₂ togive acetylated intermediate (1-1), which was followed by selectivecleavage of the amide bond between position three and position fouramino acid with trimethyloxonium tetrafluoroborate in CH₂Cl₂ to affordthe intermediate (1-2). Edman degradation of (1-2) gave the keyintermediate (1-3).

Scheme 2 illustrates a process of the preparation of a key intermediateof formular (2-6). The compound of formula (1-3), is then converted tothe compound of formula (2-1) by hydrolysis promoted with inorganic basesuch as but not limited to sodium methoxide, potassium carbonate, sodiumcarbonate, and the like. The reaction is carried out in a solvent suchas but not limited to methanol, ethanol, THF, DMF, CH₃CN. The mostpreferred solvent is methanol. The reaction temperature can vary from 0°C. to about 50° C.

Then the compound of formula (2-1) is coupled with a protected aminoacid of the formula (2-2), where R₁₁ is as previously defined to givethe compound of formula (2-3). The coupling regent can be selected from,but not limited to DCC, EDC, diisopropyl carbodiimide, BOP-Cl, PyBOP,PyAOP, TFFH and HATU. Suitable bases include, but are not limited to,triethylamine, diisopropylethylamine, DBU, N-methylmorpholine and DMAP.The coupling reaction is carried out in an aprotic solvent such as, butnot limited to, CH₂Cl₂, DMF and THF. The reaction temperature can varyfrom 0° C. to about 50° C.

The protected amino acids of formula (2-2) are prepared by the methoddescribed in Hu, T. and Panek, J. S.; J. Am. Chem. Soc. 2002, 124,11372.

The methyl ester of compound of formula (2-3) is converted to thecorresponding acid compound of formula (2-4) via alkaline hydrolysis inprotic solvents. Representative alkali compounds include lithiumhydroxide, sodium hydroxide, potassium hydroxide, and the like. Suitablesolvents include, but are not limited to, methanol, ethanol,isopropanol, butanol, THF, 1,4-dioxane and mixtures there of Thereaction temperature is preferably 0° to 35° C.

Compound of formula (2-4) is converted to the compound of formula (2-5)by acidic Boc deprotection. The acid can be selected from, but notlimited to, TFA, HCl in dioxane, methanesulfonic acid. A more throughdiscussion of the precedures, reagents and conditions for removingprotecting groups is described in literature, for example, by T. W.Greene and P. G. M. Wuts in “Protective Groups in Organic Synthesis”3^(rd) ed., John Wiley & Son, Inc., 1999.

Compound of formula (2-6) is prepared by intramolecular amide formationreaction. The regent can be selected from, but not limited to DCC, EDC,di-isopropyl carbodiimide, BOP-Cl, PyBOP, PyAOP, TFFH and HATU. Suitablebases include, but are not limited to, triethylamine,diisopropylethylamine, DBU, N-methylmorpholine and DMAP. The couplingreaction is carried out in an aprotic solvent such as, but not limitedto, CH₂Cl₂, DMF and THF. The reaction temperature can vary from 0° C. toabout 50° C.

An alternative process for the preparation of the key intermediate offormula (2-3) is also illustrated in Scheme 3.

The amino group of compound of formula (2-1) is protected by reactingwith Boc₂O in the presence of a base such as, but limited to TEA, DIPEA,DMAP, pyridine and the like. The reaction can be carried out in avariety of organic solvents such as CH₂Cl₂, toluene, Et₂O, EtOAc andchloroform. Then the hydroxyl group is protected with silylatingreagents such as, but not limited to, TMSCl, TBSCl, TESCl, TMSOTf and N,O-bis(trimethylsilyl) acetamide in the presence of an organic base.Preferably, the silylating reagent is TMSCl and N,O-bis-(trimethylsilyl)acetamide, the organic base is 1-methylimidazole.A more through discussion of the precedures, reagents and conditions forprotecting hydroxyl group is described in literature, for example, by T.W. Greene and P. G. M. Wuts in “Protective Groups in Organic Synthesis”3^(rd) ed., John Wiley & Son, Inc., 1999.

The compound of formula (3-1) is converted to the compound of formula(3-2) by hydrolysis with the essential same condition described in theconversion of (1-3) to (2-1). Further coupling of (3-2) with a protectedamino acid of formula (3-3) is proceeded using essential same conditiondescribed in the conversion of (2-1) to (2-3) to give the compound offormula (3-4).

Compound of formula (3-4) is converted to the compound of formula (3-5)by acidic N-Boc deprotection followed by ester deprotection. A throughdiscussion of the precedures, reagents and conditions for removingprotecting groups is described in literature, for example, by T. W.Greene and P. G. M. Wuts in “Protective Groups in Organic Synthesis”3^(rd) ed., John Wiley & Son, Inc., 1999.

Compound of formula (3-6) is prepared by intramolecular amide formationreaction, which is described in the conversion of (2-5) to (2-6).

Scheme 4 illustrates a process of the preparation of another keyintermediate of formular (4-6). Reduction of the compound of formula(1-3) with reducing agent such as, but not limited to NaBH₄ followed byprotection of amino group with Fmoc affords the compound of formula(4-1). The reduction is carried out in a protic solvent such as, but notlimited to, methanol, ethanol, isopropanol and tert-butanol or themixture of two protic solvents. The reaction temperature can vary from0° C. to about 50° C. Protection of the amino group with Fmoc-Cl in thepresence of organic base such as, but not limited to, triethylamine,diisopropylethylamine, DBU, N-methylmorpholine and DMAP gives thecompound of formula (4-1). The reaction is carried out in an aproticsolvent such as, but not limited to, CH₂Cl₂, DMF and THF. The reactiontemperature can vary from 0° C. to about 50° C. Further rearrangement ofthe compound of formula (4-1) in the presence of an acid, followed byacetyl protection gives the compound of formula (4-2). Suitable acidsinclude, but are not limited to, methanesufonic acid, toluenesulfonicacid, camphorsulfonic acid. The rearragement reaction is carried out ina protic solvent such as, but not limited to, methanol, ethanol,isopropanol and tert-butanol. The acetyl protection reaction is carriedout in an aprotic solvent such as, but not limited to, CH₂Cl₂,ClCH₂CH₂Cl, DMF and THF with acetic anhydride in the presence of base.The suitable bases include, but are not limited to, triethylamine,diisopropylethylamine, DBU, N-methylmorpholine and DMAP. The compound offormula (4-2) is converted to the compound of formula (4-3) with sodiummethoxide in methanol.

Then the compound of formula (4-3) is coupled with a protected dipeptideof the formula (4-4) to give the compound of formula (4-5). The couplingregent can be selected from, but not limited to DCC, EDC, di-isopropylcarbodiimide, BOP-Cl, PyBOP, PyAOP, TFFH and HATU. Suitable basesinclude, but are not limited to, triethylamine, diisopropylethylamine,DBU, N-methylmorpholine and DMAP. The coupling reaction is carried outin an aprotic solvent such as, but not limited to, CH₂Cl₂, DMF and THF.The reaction temperature can vary from 0° C. to about 50° C.

The protected dipeptides of formula (4-4) are prepared by the methoddescribed in Hu, T. and Panek, J. S.; J. Am. Chem. Soc. 2002, 124,11372.

The compound of formula (4-5) is converted to the compound of formula(4-6) by acidic Boc deprotection. The acid can be selected from, but notlimited to, TFA, HCl in dioxane, methanesulfonic acid. A more detaileddiscussion of the procedures, reagents and conditions for removingprotecting groups is described in literature, for example, by T. W.Greene and P. G. M. Wuts in “Protective Groups in Organic Synthesis”3^(rd) ed., John Wiley & Son, Inc., 1999.

The methyl ester of compound of formula (4-6) is converted to thecorresponding acid compound of formula (4-7) via alkaline hydrolysis inprotic solvents. Representative alkali compounds include lithiumhydroxide, sodium hydroxide, potassium hydroxide, and the like. Suitablesolvents include, but are not limited to, methanol, ethanol,isopropanol, butanol, THF, 1,4-dioxane and mixtures there of Thereaction temperature is preferably 0° to 35° C. Compound of formula(4-8) is prepared by intramolecular amide formation reaction. The regentcan be selected from, but not limited to DCC, EDC, di-isopropylcarbodiimide, BOP-Cl, PyBOP, PyAOP, TFFH and HATU. Suitable basesinclude, but are not limited to, triethylamine, diisopropylethylamine,DBU, N-methylmorpholine and DMAP. The coupling reaction is carried outin an aprotic solvent such as, but not limited to, CH₂Cl₂, DMF and THF.The reaction temperature can vary from 0° C. to about 50° C.

The preparation of another key intermediate is depicted in scheme 5.Aryl boronic ester of formula (5-1) is coupled with the aryl bromide offormula (5-2) using standard Suzuki coupling conditions described inAngew. Chem. Int. Ed. Engl. 2001, 40, 4544. It should be noted thatother boronic esters or boronic acid analogs of the compound of formula(5-2) may be used instead of the pinacol boronic ester. A, B, R₃, R₄,R₅, R₆ are as previeously defined. R_(p1) and R_(p2) are aminoprotecting groups such as, but not limited to, Boc and Cbz.

Compound of formula (5-3) is converted to the compound of formula (5-4)by selective deprotection of R_(p2). The selective deprotection is onlyachieved when R_(p1) and R_(p2) are different such as R_(p1) is Boc andR_(p2) is Cbz. When P_(p2) is Cbz, catalytic hydrogenation deprotectioncondition can be used. A more through discussion of the procedures,reagents and conditions for removing protecting groups is described inliterature, for example, by T. W. Greene and P. G. M. Wuts in“Protective Groups in Organic Synthesis” 3^(rd) ed., John Wiley & Son,Inc., 1999. Acylation of the compound of formula (5-4) can beaccomplished under standard acylation condition to give the compound offormula (5-5) where R₇ is as previously defined. The coupling regent canbe selected from, but not limited to DCC, EDC, di-isopropylcarbodiimide, BOP-Cl, PyBOP, PyAOP, TFFH and HATU. Suitable basesinclude, but are not limited to, triethylamine, diisopropylethylamine,DBU, N-methylmorpholine and DMAP. The coupling reaction is carried outin an aprotic solvent such as, but not limited to, CH₂Cl₂, DMF and THF.The reaction temperature can vary from 0° C. to about 50° C.Alternatively, the compound of (5-4) may be reacted with an isocyanateor carbamoyl chloride to give the compound of formula (5-5) where R₇ isan amine. The compound of formula (5-5) is converted to the compound offormula (5-6) by deprotection of R_(p1). When P_(p1) is Boc, acidicdeprotection can be used. A more through discussion of the procedures,reagents and conditions for removing protecting groups is described inthe literature, for example, by T. W. Greene and P. G. M. Wuts in“Protective Groups in Organic Synthesis” 3^(rd) ed., John Wiley & Son,Inc., 1999. Further coupling of the compound of formula (5-6) with thecompound of formula (5-7) affords the key intermediate of the compoundof formula (5-8). The coupling regent can be selected from, but notlimited to DCC, EDC, di-isopropyl carbodiimide, BOP-Cl, PyBOP, PyAOP,TFFH and HATU. Suitable bases include, but are not limited to,triethylamine, diisopropylethylamine, DBU, N-methylmorpholine and DMAP.The coupling reaction is carried out in an aprotic solvent such as, butnot limited to, CH₂Cl₂, DMF and THF. The reaction temperature can varyfrom 0° C. to about 50° C.

The preparation of compound of formula (5-1) and compound of formula(5-2) is illustrated in scheme 6. The compound of formula (5-1) may bederived from bromoketone compound of formula (6-2), which can beprepared from the corresponding ketone compound of formula (6-1) in thepresence of a bromination reagent such as NBS, bromine, or the like,optionally in the presence of an acid and/or with heating. Then thebromoketone compound of formula (6-2) may be either converted to thecorresponding amine, compound of formula (6-3), or coupled withprotected amino acid, the compound of formula (6-4) in the presence of abase such as Et₃N or DIPEA to afford keto-ester, compound of formula(6-5). Similarly, amine compound of formula (6-3) may be converted tothe corresponding keto-amide compound of formula (6-6) via condensationwith appropriate amino acid under standard amide formation conditions.Both compound of formula (6-5) and compound of formula (6-6) may betranformed to aryl bromide, the compound of formula (6-7) via heatingwith NH₄OAc under thermal or microwave conditions. The key intermediate,compound of formula (5-1) can be prepared by reacting with diboronreagent (6-9) under the Suzuki conditions which are known to thoseskilled in the art (see reviews: A. Suzuki, Pure Applied Chem. 1991, 63,419; A. Suzuki, Handbook of Organopalladium Chemistry for OrganicSynthesis 2002, 1, 249; A. Anastasia, et al, Handbook of OrganopalladiumChemistry for Organic Synthesis 2002, 1, 311; 1). Another keyintermediate the compound of formula (5-2) may be prepared from thecompound of formula (6-8) in the same fashion as the preparation of thecompound of formula (6-7).

The novel hybrid compounds of the present invention may be prepared bylinking the intermediates the compound of formula (3-6) or (4-8) withthe compound of formula (5-8). The linker can be, but not limited to,amine, ether, thioether, carbamate, urea.

An example of the linking strategies that may be used to prepare thecompounds of the present invention is shown in Scheme 7. Thehybrid-carbamate (7-3) may be prepared from the compound of formula(7-1) and the key intermediate (7-2) in the presence of condensingreagent. The condensing regent can be selected from, but not limited toCDI and phosgene. The amine (7-5) may be made by reductive aminationbetween the aldehyde (7-4) which can be derived from the compound offormula (7-1) by oxidation and the key intermediate (7-2) in thepresence of reducing reagent such as, but not limited to, sodiumcyanoborohydride. The amine (7-5) may be further transformed to thecompound of formula (7-6) by reduction amination or acylation. Theelongated hybrid compounds (7-9), which include amine, ether andthioether, may be made from the reaction of compound of formula (7-7)and corresponding neucleophiles followed by the same reaction asdescribed in the preparation of hybrid-carbamate (7-3). Theneucleophiles can be selected from, but not limited to ethanolamine,3-amino-1-propanol, 2-mercaptoethanol and 3-mercapto-1-propanol. Also,the hybrid-urea (7-12) may be made from the amine (7-11) which can besynthesized from azide (7-10).

An example of preparation of the key intermediate, compound of formula(7-2) is illustrated in scheme 8. The reaction conditions were discussedin the synthesis of intermediate (5-8). The compound of (8-9) may besynthesized from L-valine and the compound of (8-11) may be synthesizedfrom protected L-lysine.

Example 1 Compound of formula (V): where L is —OC(O)—; D is —(CH₂)₄—NH—and R₇ is

Step 1a: Compound of Formula (1-1):

CsA (481 g, 0.4 mol) was dissolved in anhydrous CH₂Cl₂ (1.8 L). Aceticanhydride (163.3 g, 1.6 mol) was added followed by DMAP (48.86 g, 0.4mol) at room temperature under nitrogen. The reaction mixture wasstirred for 36 hrs. The reaction mixture was diluted with 6 L ofisopropyl acetate, followed by 8 L of water and stirred for 30 mins. Theorganic layer was separated and washed with saturated NaHCO₃ (4×6 L) andbrine (6 L). The organic phase was dried over Na₂SO₄ and concentrated.The resulted white foam was dried under vacuum to afford the compound offormula (1-1) (520 g, 95.5% HPLC purity).

MS (ESI): 1244.8 m/z (M+1)

Step 1b: Compound of Formula (1-2):

Compound of formula (1-1) (250 g, 0.2 mole) was dissolved in anhydrousCH₂Cl₂ (2 L). Trimethyloxoniumtetrafluoroborate (89.12 g, 0.6 mol) wasadded at 0° C. and the reaction mixture was stirred at room temperaturefor 20 hrs. Methanol and water (1:1 mixture, 2.5 L) was added via adropping funnel over 15 mins at 0° C. and then stirred at roomtemperature for 3 hrs. Reaction mixture was further diluted with 2 L ofCH₂Cl₂ and 2 L of water. The organic layer was separated and washed withsaturated Na₂CO₃ (2 L) and brine (2 L), and then dried over Na₂SO₄. Thesolvent was removed and the residue was purified on silica gel column toafford the compound of formula (1-2) (170 g, 92.5% HPLC purity).

MS (ESI): 1276.8 m/z (M+1)

Step 1c: Compound of Formula (1-3):

Compound of formula (1-2) (230 g, 0.18 mole) was dissolved in anhydrousTHF (1.5 L) and Phenyl thioisocyanate (24.35 g, 0.18 mole) was addedover 15 mins at 0° C. The reaction mixture was stirred at roomtemperature for 2 hrs and diluted with 1 L of water and 2.5 L of ethylacetate. The organic layer was separated and washed with brine (1 L),and then dried over Na₂SO₄ and concentrated. After dried under vacuumfor 24 hrs, the residue was dissolved in anhydrous CH₂Cl₂ (2.66 L). TFA(455 mL) was added at 0° C. over 30 mins and the reaction mixture wasstirred at room temperature for 4 hours. Reaction was quenched withsaturated Na₂CO₃ (3 L) at −15° C. The organic layer was separated andwashed with brine (3 L), and then dried over MgSO₄. Concentrated and theresidue was purified on silica gel column to afford the compound offormula (1-3) (130 g).

Step 1d: Compound of Formula (2-1):

Compound of formula (1-3) (11.6 g, 10 mmol)) was dissolved in anhydrousMeOH (100 ml). The solution was added sodium methoxide (1.62 g, 30 mmol)and stirred at room temperature for 6 hrs. The mixture was diluted withethyl acetate (200 ml) and quenched with 1N HCl (pH ˜5). The organiclayer was separated and washed with saturated NaHCO₃ and brine, and thendried over MgSO₄. Concentrated and the residue was purified on silicagel column to afford the compound of formula (2-1) (9.8 g).

MS (ESI): 1107.8 m/z (M+1)

Step 1e: Compound of Formula (2-3):

To a 250 mL round-bottomed flask were added the compound from step 1d(0.91 g, 0.82 mmol), the compound of formula (2-2), where R₁₁ is

(347 mg, 1 mmol), CH₂Cl₂ (20 mL), BOP (437.9 mg, 0.99 mmol), and DMAP(241.9 mg, 1.98 mmol) respectively. The solution was stirred at roomtemperature for 16 hrs. Diluted with CH₂Cl₂, washed with 10% citricacid, water, saturated NaHCO₃, brine and dried over Na₂SO₄. Concentratedand the residue was purified by flash chromatography (MeOH in CH₂Cl₂,0˜20%, v/v) to afford a white solid 1.3 g.

MS (ESI): 1436.8 m/z (M+1)

Step 1f: Compound of Formula (2-4):

To a 50 mL round-bottomed flask were added the compound from step 1e(1.13 g, 0.79 mmol), THF (7 mL) and water (3 mL) respectively and thesolution was cooled to 0° C. followed by the addition of lithiumhydroxide monohydrate (100 mg, 2.4 mmol). After stirred at 0° C. for 3h, the reaction mixture was diluted with ethyl acetate (50 ml), washedwith 10% citric acid solution, brine and dried over anhydrous Na₂SO₄.The solvent was removed to give the desired product 1.0 g as white foamwhich was used for next step reaction without further purification.

MS (ESI): 1380.8 m/z (M+1)

Step 1g: Compound of Formula (2-5):

To a 50 mL round-bottomed flask were added the compound from step 1f(380 mg, 0.26 mmol) from step 1f were added CH₂Cl₂ (3 mL) and thesolution was cooled to 0° C. followed by the addition of TFA (3 mL)dropwise. The reaction mixture was stirred at 0° C. for 2 hrs and thesolvents were removed in vacuo and the residue was dissolved in CH₂Cl₂(30 mL). Washed with saturated NaHCO₃, brine and dried over anhydrousNa₂SO₄, The solvent was removed and the residue was purified by flashchromatography (MeOH/CH₂Cl₂, 1-10%, v/v) to give colorless oil 380 mg.

MS (ESI): 1280.8 m/z (M+1)

Step 1h: Compound of Formula (2-6):

To a 500 ml round-bottomed flask equipped with a dropping funnel wereadded BOP (141.5 mg, 0.32 mmol), CH₂Cl₂ (250 ml) followed by addition ofa solution of DMAP (39.1 mg, 0.32 mmol) and the compound from step 1g(200 mg, 0.16 mmol) in CH₂Cl₂ (100 mL) during 2 hrs at room temperature.The solution was stirred at room temperature for 16 hrs. The reactionwas quenched with saturated NaHCO₃. The organic layer was separated andwashed with brine dried over anhydrous Na₂SO₄. The solvent was removedand the residue was purified by flash chromatography (MeOH/CH₂Cl₂,1-10%, v/v) to give a white solid 134 mg.

MS (ESI): 1262.9 m/z (M+1)

Step 1i: Compound of Formula (8-9)

To a mixture of L-Valine (3.9 g, 33.29 mmol) in 1M-NaOH (33 mL, 33 mmol)was added Na₂CO₃ (1.83 g, 17.2 mmol) and cooled to 0° C. Methylchloroformate (2.8 mL, 36.1 mmol) was slowly added to the reactionmixture at 0° C. for 10 min. and allowed to warm to room temperature andstirred for 3 hours. The reaction mixture was washed with diethyl ether(3×10 mL). The aqueous layer was cooled to 0° C. and acidified withconcentrated HCl to pH (˜2) and extracted with methylene chloride (3×30mL). The combined organic layer was washed with brine, dried overNa₂SO₄, filtered, evaporated and dried on vacuum pump to give the titlecompound (5.3 g) as a white power.

Step 1j: Compound of Formula (8-12)

To a mixture of (8-11) (1.011 g, 2.15 mmol) in anhydrous methylenechloride (7 mL) was added HCl (14 mL, 4M in 1,4-dioxane) was dropwiseadded at room temperature and stirred for 1.5 hours. It was evaporatedoff and dried on vacuum pump to give HCl salt as a white solid. To amixture of HCl salt in methylene chloride (27 mL) was addeddiisopropylethylamine (1.13 mL, 6.47 mmol) and methyl chloroformate(0.17 mL, 2.27 mmol) successively at 0° C. and stirred at roomtemperature for 1.5 hours. The reaction mixture was diluted withmethylene chloride (70 mL), washed with 1M-HCl, H₂O and brine. Theorganic layer was dried over Na₂SO₄, filtered and evaporated to dryness.The residue was purified by SiO₂ column chromatography using 0-15%methanol in methylene chloride to give the title compound (0.6 g) as awhite solid. MS: (ESI) m/z (M+H) 427.30.

Step 1k: Compound of Formula (8-4)

To a mixture of 1,4-dibromoacetophenone (8-1)(7.0 g, 25.19 mmol) andCbz-L-proline (8-2) (6.59 g, 26.45 mmol) in acetonitrile (65 mL) wasadded diisopropylethylamine (5.27 mL, 30.23 mmol) and stirred at roomtemperature for 1.5 hours. The reaction was evaporated off, diluted withethylacetate (100 mL), washed with aqueous saturated NaHCO₃ solution andbrine. The organic layer was dried over Na₂SO₄, filtered and evaporatedto give a brownish solid (˜12 g), which was used directly for the nextreaction without further purification. A mixture of previously obtainedbrownish solid (˜12 g) and ammonium acetate (19.42 g, 252 mmol) intoluene (74 mL) was heated at 100° C. for 16.5 hours. After cooling toroom temperature, the reaction mixture was treated with saturatedaqueous NaHCO₃ solution (pH ˜9), extracted with ethyl acetate (3×50 mL).The combined organic layer was washed with H₂O and brine, dried overNa₂SO₄, filtered and evaporated to dryness. The residue was purified bySiO₂ column chromatography using 0-60% ethyl acetate in hexanes to givethe title compound (8-4) (9.7 g) as a pale brownish form. MS: (ESI) m/z(M+H) 426.23, 428.23.

Step 1l: Compound of Formula (8-5)

The compound of formula (8-5) may be prepared in the same fashion as thepreparation of the compound of formula (8-4).

Step 1m: Compound of Formula (8-6)

A mixture of the compound of formula (8-5) (5.0 g, 12.74 mmol),bis-(pinacolato)diboron (3.59 g, 14.01 mmol) and potassium acetate (1.88g, 19.1 mmol) in 1,4-dioxane (42 mL) was degassed. Pd(PPh₃)₄ (735 mg,0.64 mmol) was added to the reaction and degassed again. The reactionmixture was heated at 80° C. for 14.5 hours. It was diluted with ethylacetate (200 mL) and washed with saturated aqueous NaHCO₃ solution. Theaqueous layer was extracted with ethyl acetate (2×100 mL). The combinedorganic layer was washed with H₂O and brine, dried over Na₂SO₄, filteredand evaporated to dryness. The residue was purified by SiO₂ columnchromatography using 0-60% ethyl acetate in hexanes to give the titlecompound (8-6) (4.184 g) as a pale yellow solid. MS: (ESI) m/z (M+H)440.30.

Step 1n: Compound of Formula (8-7)

A mixture of boronic ester, the compound of formula (8-6) (1 g, 2.28mmol), arylbromide, the compound of formula (8-5) (1.02 g, 2.39 mmol)and NaHCO₃ (630 mg, 7.51 mmol) in DME-H₂O (3:1, 24 mL) was degassed andPd(PPh₃)₄ (138 mg, 0.12 mmol) was added to the reaction and degassedagain. The reaction mixture was heated at 80° C. for 14 hours. It wasfiltered through a fritted funnel and evaporated off. The residue wasdiluted with methylene chloride and H₂O. The aqueous layer was extractedwith methylene chloride. The combined organic layer was washed with H₂Oand brine, dried over Na₂SO₄, filtered and evaporated to dryness. Theresidue was purified by SiO₂ column chromatography using 30-100% ethylacetate containing 1% triethylamine in hexanes to give the titlecompound (8-7) (0.662 g) as a pale yellow solid. MS: (ESI) m/z (M+H)659.29.

Step 1o: Compound of Formula (8-8)

A mixture of the compound of formula (8-7) (1.78 g, 2.7 mmol), 10% Pd—C(371 mg), K₂CO₃ (336 mg) and H₂O (6 drops) in EtOH (50 mL) wasvigorously stirred under H2 atmopsphere (using balloon) for 6 hours.Then, 10% Pd—C (120 mg) and K₂CO₃ (120 mg) were additionally added tothe reaction and vigorously stirred for 2 hours. It was filtered througha pad of celite and evaporated to dryness. The residue was purified bySiO₂ column chromatography using 0-25% methanol in methylene chloride togive the title compound the compound of formula (8-8) (1.204 g) as apale yellow solid.

MS: (ESI) m/z (M+H) 525.29.

Step 1p: Compound of Formula (8-10)

To a mixture of the compound of formula (8-8) (1.2 g, 2.28 mmol), thecompound of formula (8-9) (440 mg, 2.51 mmol) and diisopropylethylamine(1.2 mL, 6.84 mmol) in anhydrous methylene chloride (23 mL) wasportionwise added HATU (955 mg, 2.51 mmol) at room temperature andstirred for 1.5 hours. The reaction mixture was diluted with methylenechloride (30 mL), washed with saturated aqueous NaHCO₃ Solution, H₂O andbrine, dried over Na₂SO₄, filtered and evaporated to dryness. Theresidue was dissolved in methanol 15 mL), treated with K₂CO₃ (315 mg)and stirred for 1 hour. The reaction was filtered through a frittedfunnel and evaporated to dryness. The residue was purified by SiO₂column chromatography using 0-4% methanol in methylene chloride to givethe title compound (8-10) (1.366 g) as a pale yellow foam. MS: (ESI) m/z(M+H) 682.56.

Step 1q: Compound of Formula (8-13)

To a mixture of the compound of formula (8-10) (300 mg, 0.44 mmol) inanhydrous methylene chloride (1 mL) was added HCl (4 mL, 4M in1,4-dioxane) and stirred for 1.5 hour. The reaction was evaporated offand dried on vacuum pump to give a HCl salt. To a mixture of HCl saltpreviously obtained and the compound of formula (8-12) (216 mg, 0.51mmol) in methylene chloride (8 mL) was added diisopropylethylamine (0.54mL, 3.08 mmol) at 0° C. followed by addition of HATU (192 mg, 0.51 mmol)and stirred for at room temperature for 2 hours. The reaction mixturewas diluted with methylene chloride (10 mL), washed with saturatedaqueous NaHCO₃ solution, H₂O and brine, dried over Na₂SO₄, filtered andevaporated to dryness. The residue was dissolved in methanol (10 mL),treated with K₂CO₃ (12 mg) and stirred for 30 min. The reaction wasfiltered through a fitted funnel and evaporated to dryness. The residuewas purified by SiO₂ column chromatography using 0-4% methanol inmethylene chloride to give the title compound (8-13) (401 mg) as a paleyellow foam. MS: (ESI) m/z (M+H) 990.52.

Step 1r: Compound of Formula (8-14)

To a mixture of the compound of formula (8-13) (200 mg, 0.2 mmol) inanhydrous THF (2 mL) was added piperidine (0.2 mL, 2 mmol) at roomtemperature and stirred for 2.5 hours. The reaction mixture wasevaporated, dissolved in methylene chloride (1 mL) and toluene (2 mL),evaporated to dryness. The residue was purified by SiO₂ columnchromatography using 0-20% methanol (2N—NH₃) in methylene chloride togive the title compound (8-14) (145 mg) as a pale yellow foam. MS: (ESI)m/z (M+H) 768.81.

Step 1s: Compound of Formula (7-3): where L is —O(CO)—, R₈ is H and R₇is

A mixture of alcohol (2-6) (101 mg, 0.08 mmol) and CDI (13 mg, 0.08mmol) in anhydrous acetonitrile (0.73 mL) was stirred at roomtemperature for 1 hour. Then, compound of formula (8-14) (56 mg, 0.073mmol) and DBU (11 μL, 0.073 mmol) were added to the reaction and heatedat 60° C. for 2 hour. It was evaporated to dryness. The residue waspassed through a short silica gel column using 0-8% methanol inmethylene chloride to give a colorless solid (56 mg), which was purifiedby RP-HPLC using 30-90% acetonitrile in 10mM NH₄HCO₃ buffer as a mobilephase. The combined fraction was evaporated in vacuo and lyophilized toafford the title compound (7-3) as a white powder. MS: (ESI) m/z (M+H)2057.74.

Example 2 Compound of Formula (VI): where L is —OC(O)—; D is —(CH₂)₄—NH—and R₇ is

Step 2a: Compound of Formula (4-1):

Compound of formula (1-3) (61 g, 53 mmole) was dissolved in isopropanol(450 ml) and methanol (50 ml), and NaBH₄ (9.0 g, 266 mmole) was addedduring 1 hrs 1 at 0° C. The reaction mixture was stirred at roomtemperature for 2 hrs. Ethyl acetate (50 ml) was added and the mixturewas stirred at room temperature for 30 min and then quenched with 1N HClat 0° C. The pH of mixture was adjusted to pH ˜9 by adding saturatedNaHCO₃ and Na₂CO₃. Extracted with ethyl acetate and washed withsaturated NaHCO₃ and brine. Dried over Na₂SO₄ and the solvent wasremoved. The residue was dried on vaccum to give the alcohol compound(59.7 g). Then the resulted compound was dissolved in DCM (500 ml).FmocCl (11.7 g, 45 mmole) and DIPEA (12.9 g, 100 mmol) were added at 0°C. The reaction mixture was stirred at 0° C. for 2 hrs. Diluted with DCM(500 ml) and washed with 10% citric acid, saturated NaHCO₃ and brine.Dried over Na₂SO₄ and the solvent was removed. The residue was purifiedon by silica gel column to give the compound of formula (4-1) (46 g).MS: (ESI) m/z (M+H) 1343.8.

Step 2b: Compound of Formula (4-2):

Compound of formula (4-1) (13.4 g, 10 mmole) was dissolved inisopropanol (100 ml). Methanesulfonic acid (100 mmole) was added at roomtemperature. The reaction mixture was stirred at 50° C. for 8 hrs. Thereaction mixture was condensed to ˜40 ml and was diluted with ethylacetate (500 ml) and quenched with saturated NaHCO₃. The pH of themixture was further adjusted to ˜9 by adding saturated Na₂CO₃. Theorganic layer was seperated and washed with brine. Dried over Na₂SO₄ andthe solvent was removed. The residue was dissolved in DCM (100 ml) andwas added acetic anhydride (2.04 g, 20 mmol) followed by TEA (4.04 g, 40mmol). The mixture was stirred at room temperature for 3 hrs andquenched with saturated NaHCO₃. The organic layer was seperated andwashed with brine. Dried over Na₂SO₄ and concentrated. The residue waspurified on by silica gel column to give the compound of formula (4-2)(10 g). MS: (ESI) m/z (M+H) 1385.8.

Step 2c: Compound of Formula (4-3):

Compound of formula (4-2) (6.9 g, 5 mmole) was dissolved in methanol (50ml). NaOMe (2N in methanol, 25 ml) was added at room temperature. Thereaction mixture was stirred at room temperature for 18 hrs and quenchedwith saturated NaHCO₃. The pH of the mixture was further adjusted to ˜9by adding saturated Na₂CO₃. Organic layer was seperated and washed withbrine. Dried over Na₂SO₄ and the solvent was removed. The residue waspurified on by silica gel column to give the compound of formula (4-3)(4.2 g). MS: (ESI) m/z (M+H) 1036.7.

Step 2d: Compound of Formula (4-5):

To a 250 mL round-bottomed flask were added the compound of formula(4-3) (1.04 g, 1.0 mmol), the compound of formula (4-4), where R₁₁ is

(475 mg, 1.1 mmol), CH₂Cl₂ (20 mL), BOP (531 mg, 1.2 mmol), and DMAP(241.9 mg, 1.98 mmol) respectively. The solution was stirred at roomtemperature for 16 hrs. Diluted with CH₂Cl₂, washed with 10% citricacid, water, saturated NaHCO₃, brine and dried over Na₂SO₄. Concentratedand the residue was purified by flash chromatography (MeOH in CH₂Cl₂,0˜20%, v/v) to afford a white solid 1.4 g.

MS (ESI): 1450.8 m/z (M+1)

Step 2e: Compound of Formula (4-6):

To a 50 mL round-bottomed flask were added the compound of formula (4-5)(725 mg, 0.50 mmol) from step 2d were added CH₂Cl₂ (3 mL) and thesolution was cooled to 0° C. followed by the addition of TFA (3 mL)dropwise. The reaction mixture was stirred at 0° C. for 2 hrs and thesolvents were removed in vacuo and the residue was dissolved in CH₂Cl₂(30 mL). Washed with saturated NaHCO₃, brine and dried over anhydrousNa₂SO₄, The solvent was removed and the residue was purified by flashchromatography (MeOH/CH₂Cl₂, 1-10%, v/v) to give colorless oil 730 mg.

MS (ESI): 1350.8 m/z (M+1)

Step 2f: Compound of Formula (4-7):

To a 50 mL round-bottomed flask were added the compound from step 2e(675 mg, 0.5 mmol), THF (7 mL) and water (3 mL) respectively and thesolution was cooled to 0° C. followed by the addition of lithiumhydroxide monohydrate (100 mg, 2.4 mmol). After stirred at 0° C. for 3h, the reaction mixture was diluted with ethyl acetate (50 ml), washedwith 10% citric acid solution, brine and dried over anhydrous Na₂SO₄.The solvent was removed to give the desired product 650 mg as white foamwhich was used for next step reaction without further purification.

MS (ESI): 1294.8 m/z (M+1)

Step 2g: Compound of Formula (4-8):

To a 500 ml round-bottomed flask equipped with a dropping funnel wereadded BOP (141.5 mg, 0.32 mmol), CH₂Cl₂ (250 ml) followed by addition ofa solution of DMAP (39.1 mg, 0.32 mmol) and the compound from step 2f(200 mg, 0.16 mmol) in CH₂Cl₂ (100 mL) during 2 hrs at room temperature.The solution was stirred at room temperature for 16 hrs. The reactionwas quenched with saturated NaHCO₃. The organic layer was separated andwashed with brine dried over anhydrous Na₂SO₄. The solvent was removedand the residue was purified by flash chromatography (MeOH/CH₂Cl₂,1-10%, v/v) to give a white solid 134 mg.

MS (ESI): 1276.9 m/z (M+1)

Step2h: Compound of Formula (7-3): where L is —O(CO)—, R₈ is Me and R₇is

A mixture of the compound of formula (4-8) (60 mg, 0.042 mmol) and CDI(8.2 mg, 0.051 mmol) in anhydrous methylene chloride (0.42 mL) wasstirred at room temperature for 1 hour. Then, amine, compound of formula(8-14) (30.7 mg, 0.04 mmol) and DBU (6.3 μL, 0.042 mmol) were added tothe reaction and stirred at room temperature for 15 hours. Afterremoving the solvent, acetonitrile (0.4 mL) was added to the reactionand heated at 70° C. for 3 hours. It was evaporated to dryness. Theresidue was passed through a short silica gel column using 0-10%methanol in methylene chloride to give a colorless solid (43.7 mg),which was purified by RP-HPLC using 30-90% acetonitrile in 10 mM NH₄HCO₃buffer as a mobile phase. The combined fraction was evaporated in vacuoand lyophilized to afford the title compound (7-3) as a white powder.MS: (ESI) m/z (M+H) 2071.74.

Example compounds 3-221, wherein R₇ are delineated for each example inthe following table are prepared via the method delineated in example 1.

        example

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Example compounds 222-440, wherein R₇ are delineated for each example inthe following table are prepared via the method delineated in example 2.

        example

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What is claimed is:
 1. A compound represented by the formula (I):

or a pharmaceutically acceptable salt, ester or prodrug thereof,wherein: Ring A and ring B are each independently selected from: a)Phenyl; b) Substituted phenyl; c) Six membered heteroaryl containingone, two or three nitrogen atoms; and d) Substituted six memberedheteroaryl containing one, two or three nitrogen atoms; R₁ and R₂ areeach independently selected from: a) Hydrogen; b) Deuterium; c) Halogen;d) R₁₁, where is selected from: 1) C₁-C₁₂ alkyl; 2) Substituted C₁-C₁₂alkyl; 3) C₂-C₁₂ alkenyl; 4) Substituted C₂-C₁₂ alkenyl; 5) C₂-C₁₂alkynyl; 6) Substituted C₂-C₁₂ alkynyl; 7) C₃-C₁₂ cycloalkyl; 8)Substituted C₃-C₁₂ cycloalkyl; 9) Aryl; 10) Substituted aryl; 11)Heterocycloalkyl; 12) Substituted heterocycloalkyl; 13) Heteroaryl; or14) Substituted heteroaryl; e) —C(O)OR₁₂, where R₁₂ is selected fromhydrogen or R₁₁ where R₁₁ as previously defined; f) —C(O)R₁₂, where R₁₂is as previously defined; g) —C(O)N(R₁₃)(R₁₄), where R₁₃ and R₁₄ areindependently selected from R₁₂ and R₁₂ is as previously defined or R₁₃and R₁₄ combined together with the N which attached to is substituted orunsubstituted heterocycloalkyl; h) —C(O)SR₁₂, where R₁₂ is as previouslydefined; i) —C(S)O R₁₂, where R₁₂ is as previously defined; j) —C(S)SR₁₂, where R₁₂ is as previously defined; k) —OR₁₂, where R₁₂ is aspreviously defined; l) —SR₁₂, where R₁₂ is as previously defined; and m)—NR₁₃R₁₄, where R₁₃ and R₁₄ are as previously defined; R₃, R₄, R₅ and R₆are each independently selected from: a) Hydrogen; b) Deuterium; c)C₁-C₁₂ alkyl; d) Substituted C₁-C₁₂ alkyl; e) C₂-C₁₂ alkenyl; f)Substituted C₂-C₁₂ alkenyl; g) C₂-C₁₂ alkynyl; h) Substituted C₂-C₁₂alkynyl; i) C₃-C₁₂ cycloalkyl; j) Substituted C₃-C₁₂ cycloalkyl; k)Aryl; l) Substituted aryl; m) Heterocycloalkyl; n) Substitutedheterocycloalkyl; o) Heteroaryl; and p) Substituted heteroaryl; or R₃and R₅, together with the nitrogen atom and the carbon atom to whichthey are attached, and/or R₄ and R₆, together with the nitrogen atom andthe carbon atom to which they are attached independently form asubstituted or unsubstituted heterocycloalkyl; R^(a) and R^(b) areindependently selected from: a) Hydrogen; b) R₁₁; c) —C(O)O—R₁₁, whereR₁₁ is as previously defined; d) —C(O)NHR₁₁, where R₁₁ is as previouslydefined; or R^(a) and R^(b), together with the nitrogen atom to whichthey are attached, form a substituted or unsubstituted heterocycloalkyl;R₇ is selected from: a) R₁₁, where R₁₁ is as previously defined; b)—OR₁₁, where R₁₁ is as previously defined; c) —SR₁₁, where R₁₁ is aspreviously defined; and d) —NR₁₃R₁₄, where R₁₃ and R₁₄ are as previouslydefined; D and E are each independently selected from: a) C₁-C₁₂alkylene containing 0, 1, 2 or 3 heteroatoms independently selected fromO, S and N; b) Substituted C₁-C₁₂ alkylene containing 0, 1, 2 or 3heteroatoms independently selected from O, S and N; c) C₂-C₁₂ alkenylenecontaining 0, 1, 2 or 3 heteroatoms independently selected from O, S andN; d) Substituted C₂-C₁₂ alkenylene containing 0, 1, 2 or 3 heteroatomsindependently selected from O, S and N; e) C₂-C₁₂ alkynylene containing0, 1, 2 or 3 heteroatoms independently selected from O, S and N; f)Substituted C₂-C₁₂ alkynylene containing 0, 1, 2 or 3 heteroatomsindependently selected from O, S and N; g) C₃-C₁₂ cycloalkylene; h)Substituted C₃-C₁₂ cycloalkylene; i) Heterocycloalkylene; and j)Substituted heterocycloalkylene; L is absent, or selected from: a) —O—;b) —N(R₁₂)—; where R₁₂ is as previously defined; c) —N(C(O)R_(ii))—;where R₁₁ is as previously defined; d) —N(C(O)OR₁₁)—; where R₁₁ is aspreviously defined; e) —S(O)_(m)—, where m=0, 1 or 2; f) —OC(O)NH—; g)—OC(S)NH—; h) —SC(S)NH—; i) —NHC(O)NH—; j) —NHC(S)NH—; k) —O-M-, where Mis selected from optionally substituted C₁-C₁₂ alkylene, or optionallysubstituted C₂-C₁₂ alkenylene, or optionally substituted C₂-C₁₂alkynylene, or optionally substituted C₃-C₁₂ cycloalkylene; l)—S(O)_(m)-M-, where m=0, or 1, or 2 and M is as previously defined; m)—OC(O)NH-M-, where M is as previously defined; n) —OC(S)NH-M-, where Mis as previously defined; o) —NHC(O)NH-M-, where M is as previouslydefined; and p) —NHC(S)NH-M-, where M is as previously defined; J isR₁₁, where R₁₁ is as previously defined; K is ethyl, 1-hydroxyethyl,isopropyl or n-propyl; R₈ is selected from: a) Hydrogen b) C₁-C₁₂ alkyl;and c) Substituted C₁-C₁₂ alkyl; R^(c) is methyl, ethyl, allyl orn-propyl; and R₉ is hydrogen or R₁₁.
 2. A compound according to claim 1which is represented by the formula (II):

wherein, R₃, R₄, R₅, R₆, R₇, R₈, R^(a), R^(b), E, L, and D are asdefined in claim
 1. 3. A compound according to claim 1 which isrepresented by the formula (III):

wherein, R₇, R₈, R^(a), R^(b), E, L, and D are as defined in claim
 1. 4.A compound according to claim 1 which is represented by the formula(IV):

wherein, R₈, E, L, and D are as defined in claim
 1. 5. A compoundrepresented by formula (V) or formula (VI):

wherein: L is selected from: —N(Me)—; —NH—; —N(Boc)-; —N(Ac)-;—OC(O)NH—, —SCH₂CH₂OC(O)NH— and —OCH₂CH₂OC(O)NH—; n is 0, 1, 2, 3, 4 or5; and R₇C(O)— is selected from the groups set forth in the followingtable: Entry

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6. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1 or a pharmaceutically-acceptable salt,ester or prodrug thereof, in combination with a pharmaceuticallyacceptable carrier.
 7. A method of treating a viral infection in asubject in need thereof, comprising administering to said subject atherapeutically-effective amount of the pharmaceutical compositionaccording to claim
 6. 8. The method according to claim 7 wherein saidviral infection is selected from HCV, HBV, HAV and HIV infection.
 9. Themethod of claim 8 further comprising coadministering at least oneadditional anti-viral agent.
 10. The method of claim 8 wherein saidadditional anti-viral agent is selected from viral-enzyme targetedcompounds, viral-genome-targeted therapies, and immunomodulatory agents.11. The method of claim 8 further comprising coadministering acytochrome P-450 inhibitor.
 12. The method of claim 10, wherein theadditional anti-viral compound is selected from ribavirin, interferonand Toll receptor agonists.
 13. The method of claim 11, wherein thecytochrome P-450 inhibitor is ritonavir.